Schizophrenia is a life-long mental illness with variable expression and unknown etiology. The major clinical manifestations of schizophrenia at disease onset are psychotic symptoms; however, as the illness progresses the negative symptoms become more predominant. In addition, many other neurological aspects change over the course of illness. The molecular factors that influence symptom presentation and the course of schizophrenia after its onset and how treatment modifies the effects of illness remain important and essentially unaddressed questions. Our goals in this application are to identify genes that have altered levels of expression in the CNS of individual subjects who have had a short or long duration of illness using the automate method Total Gene expression Analysis (TOGA*/R). We will generate gene expression profiles from the prefrontal and temporal cortices of individual schizophrenic subjects at different stages of illness: 10 acute schizophrenic subjects (illness duration <5 yrs), 10 chronic schizophrenic subjects (illness duration >22 yrs) and 20 controls, age- and sex- matched to both disease cohorts (n=80 expression profiles total). Since correct treatment early in the illness is thought to have a beneficial affect on the outcome of the disease, the identification of genes involved in the early versus late stages of disease will be important for understanding disease progression. We will also investigate disease heterogeneity in the schizophrenia syndrome by distinguishing gene expression patterns that are present in subsets of all schizophrenic individuals. We will further characterize how the expression of antipsychotic drug-regulated genes (previously identified in mice) is altered in human subjects with schizophrenia in order to elucidate potential consequences of antipsychotic drug exposure in humans. This will be accomplished by measuring expression differences of candidate genes in postmortem brain samples from chronic schizophrenic subjects by real-time PCR, in situ hybridization and Western blot analyses. Overall, these studies may lead to approaches that will favorably alter the course, treatment and outcome of schizophrenia.